Summary of work: The neuroanatomic and neurophysiologic underpinnings of age-associated cognitive and memory change remain unclear, as there are a limited number of studies of longitudinal brain changes in individuals without dementia. We are performing serial magnetic resonance imaging (MRI), positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change. These evaluations allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's Disease (AD). An understanding of these associations and early detection of brain changes will be critical in identifying individuals likely to benefit from new interventions. Since 2005, we also have acquired 11-C-PIB PET imaging studies of amyloid distribution in the brain to enhance the identification of preclinical AD. In addition, we are using neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in brain aging, genetic risk factors and the effects of sex steroid and other hormones. [unreadable] [unreadable] We continued the development and validation of new tools for processing images for longitudinal studies. We published a number of papers investigating longitudinal age changes in regional cerebral blood flow (rCBF) to characterize patterns of change in functional activity in cognitively stable older adults(Beason-Held et al., Neurobiology of Aging, 2008; epub 2006). We evaluated rCBF during rest and delayed verbal and figural recognition memory tasks at year 1 baseline and at year 9 in 25 BLSA participants who had maintained cognitive and physical health over the 8-year follow-up. We investigated changes over time that were common across all three conditions and changes that were specific to either verbal or figural memory conditions. Changes common to all scan conditions, as well as changes specific to either verbal or figural memory, were observed, and these changes reflected both regional increases and decreases in activity over time. In a second paper, we investigated the temporal patterns of these changes over time, investigating both linear and non-linear changes in rCBF patterns(Beason-Held et al., Neurobiology of Aging, 2008; epub 2006). Using data from Years 1, 3, 5, 7, and 9 from the 25 participants who maintained cognitive and physical health, we found that many brain regions showed steady, progressive changes in rCBF over the 8 years while others maintained rCBF for a number of years before showing incremental declines or increases in activity, particularly in the frontal and temporal lobes of the brain. These findings suggest that there are distinctive patterns of age-related functional decline and compensatory activity over time in healthy, cognitively stable individuals, many of which involve regions that are crucial for memory and other higher order cognitive functions. The characterization of these patterns in cognitively normal individuals will aide distinguishing normal from pathological patterns of age-related functional change. [unreadable] [unreadable] We also investigated modifiers of these functional brain changes over time, comparing changes in functional activity for individuals without hypertension to those with treated hypertension (Beason-Held et al, Stroke, 2007). Relative to those without hypertension, the hypertension group showed greater rCBF decreases in prefrontal, anterior cingulate and occipital areas over time, suggesting that these regions are more susceptible to hypertension-related dysfunction with advancing age. In another paper, we compared longitudinal rCBF changes over time in older BLSA participants who had stable (n=38) and progressively worsening (n=36) MRI white matter signal abnormalities over a period of approximately 8 years (Kraut et al., Journal of Cerebral Blood Flow and Metabolism, 2008; epub 2007). Individuals with progressively worsening white matter abnormalities exhibited a different relationship between patterns of rCBF and severity of white matter abnormalities early in the development of these abnormalities and a different pattern of longitudinal change over time compared to those whose ratings of signal abnormalities remain stable. In combination, these results show that vascular disease may modify longitudinal changes in brain function in older adults.[unreadable] [unreadable] A major emphasis of our work over the last year has been the application of support vector machine learning algorithms to structural and functional imaging data to improve discrimination of cognitively normal from cognitively impaired individuals on an individual person-basis. We published the first application of this approach to cognitive impairment using structural MRI data from 15 individuals with mild cognitive impairment (MCI) and 15 cognitively normal individuals matched for age, sex, and race (Davatzikos et al. Neurobiology of Aging, 2008; epub 2006). We demonstrated 90% classification accuracy using a single MRI scan and showed greater longitudinal increase in the abnormality score for the MCI compared with normal subjects. In a second study, we showed that adding information from a resting PET rCBF scan to the structural MRI improved classification accuracy to 93% (Fan et al., NeuroImage 2008). [unreadable] [unreadable] Using the 11-C-PIB PET scan data, we confirmed the experience at other centers that 20-30% of cognitively normal older adults have PIB positive scans, i.e., deposition of brain amyloid. In addition, we investigated whether PIB retention was associated with longitudinal rCBF changes in the preceding years (Sojkova et al., Journal of Nuclear Medicine, in press). PIB distribution volume ratios (DVR) of regions of interest were estimated by fitting a reference tissue model to the measured time activity curves, using the approach published in collaboration with Dr. Yun Zhou of Johns Hopkins (Zhou et al, Neuroimage, 2007). The mean cortical DVR was used to divide participants into high and low PIB retention groups. Greater longitudinal decreases in rCBF in the high PIB group were seen in right anterior/mid cingulate, right supramarginal gyrus, left thalamus and midbrain bilaterally relative to the low group. Greater increases in rCBF over time in the high PIB group were found in left medial and inferior frontal gyri, right precuneus, left inferior parietal lobule, and the left postcentral gyrus. While longitudinal declines may reflect greater decrements in neuronal function in the high PIB group, greater longitudinal increases in rCBF are also observed in those with higher amyloid load and may represent a compensatory attempt to preserve neuronal function in these regions.